image: PI3K signaling pathways. Upon activation by RTK, GPCR, Integrin, and Ras, p110 loses inhibition by p85 and converts PIP2 to PIP3. PIP3 recruits AKT to the cell membrane, where AKT is activated through phosphorylation by PDK1 at T308 and by mTORC2 at S473. Activated AKT phosphorylates TSC1/2 and relieves its inhibition function on mTORC1, promoting protein translation. AKT also phosphorylates and inhibits GSK3β, initiating glucose metabolism and glycogen synthesis. AKT regulates the cell cycle by phosphorylating FoxO1 and decreasing its transcription of CDK inhibitors p21 and p27. AKT, protein kinase B; CDK, cyclin dependent kinase; FoxO1, forkhead box O1; GPCR, G-protein coupled receptor; GSK3β, glycogen synthase kinase 3β; mTORC1/2, mammalian target of rapamycin complex 1/2; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; RTK, receptor tyrosine kinase; TSC1/2, tuberous sclerosis complex 1/2. Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304224002277-gr1_lrg.jpg
Credit: The authors
A newly published review in Genes & Diseases explores the oncogenic activation of PIK3CA in cancer and highlights emerging targeted therapies designed to improve treatment efficacy while reducing side effects. The research provides a comprehensive analysis of PIK3CA mutations, their role in tumor development, and novel therapeutic approaches currently in development.
The PIK3CA gene, which encodes the p110α subunit of phosphoinositide 3-kinase (PI3K), is among the most frequently mutated oncogenes in cancer. These mutations drive tumor progression, metabolic reprogramming, and resistance to existing treatments, making them a prime target for precision oncology. While current FDA-approved PI3Kα inhibitors, such as alpelisib, have demonstrated success in treating hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer, their clinical effectiveness is often restricted by dose-limiting side effects, including hyperglycemia.
The review highlights next-generation therapies that specifically target PIK3CA mutations with improved selectivity and reduced toxicity. Several promising inhibitors, including RLY-2608, STX-478, and LOXO-783, have demonstrated potential in preclinical and clinical trials. These therapies aim to overcome the limitations of existing treatments by selectively inhibiting mutant PI3Kα without affecting normal PI3K activity, reducing adverse effects and enhancing patient outcomes.
In addition to drug development, the study explores how PIK3CA mutations alter tumor metabolism, enhance immune evasion, and reshape the tumor microenvironment. These insights are paving the way for combination therapies that integrate PI3K inhibitors with immunotherapy and metabolic drugs to improve response rates and durability of treatment.
With continued advancements in precision oncology, PIK3CA-mutated cancers are now at the forefront of innovative treatment strategies. The development of mutant-selective therapies marks a significant step toward more effective and personalized cancer care.
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Yuxiang Wang, Valery Rozen, Yiqing Zhao, Zhenghe Wang, Oncogenic activation of PIK3CA in cancers: Emerging targeted therapies in precision oncology, Genes & Diseases, Volume 12, Issue 2, 2025, 101430, https://doi.org/10.1016/j.gendis.2024.101430
Journal
Genes & Diseases